1 INTRODUCTION
Baloxavir marboxil—an inhibitor of influenza cap-dependent
endonuclease—is a new class of antiviral drug against seasonal
influenza [1,2]. In 2018, baloxavir was approved in Japan and the US
[3]; the drug was first approved for the indication for otherwise
healthy persons with uncomplicated influenza, but the indication has now
expanded to persons at high-risk of influenza complications [4].
Baloxavir was estimated to have been prescribed for more than five
million persons during the 2018/2019 influenza season in Japan,
representing 40% of all antivirals prescribed in the country for
influenza [5].
In prelicensure phase 2/3 trials, the clinical efficacy of baloxavir was
superior to that of a placebo and similar to that of oseltamivir, with
respect to symptom duration [6]. However, viral mutations conferring
less susceptibility to baloxavir—amino acid substitutions at position
38 of polymerase acidic protein—were reported in 2.2% of 182 and
9.7% of 370 baloxavir recipients in the phase 2 and 3 trials,
respectively. This group of patients experienced a longer median time to
alleviation of symptoms than baloxavir recipients without shedding
variant strain [7]. According to surveillance data from the
2018/2019 season in Japan, 1.7% (6/343) of A (H1N1) strain and 9.5%
(34/357) of A (H3N2) strain exhibited reduced susceptibility to
baloxavir from specimens obtained from both treated and untreated
persons [8]. This raises a concern for high proportion of variant
virus and changes in the clinical course of affected cases [9].
However, the clinical consequence of variant virus is not fully
understood in clinical and public health perspective, due to the sparse
data of this novel drug from non-trial setting.
In this study, we hypothesized that baloxavir recipients shedding
variant virus less susceptible to this drug utilized more medical
resources if their symptoms were subsequently prolonged. Using a
large-scale observational data in Japan, we sought to assess the
association between baloxavir use and subsequent medical resource use
among children, a group in which the risk of the virus developing
reduced susceptibility to baloxavir is high [10].